A biocide is a chemical substance, which can deter, render harmless, or exert a controlling effect on any harmful organism. Biocides are commonly used in medicine, agriculture, forestry, and industry.
The development of new and useful biocides requires consideration of many elements such as the following: the type of organism whose control is desired; the manner in which the biocide is to be deployed; the costs of preparing and delivering the biocide; environmental or disposal issues; and so on. Depending on the potential use envisioned, primary considerations are likely to include both its potency against the organisms targeted, as well as its biocompatibility, e.g. lack of toxicity against the humans or animals which may come into contact with it. Biocides may have a broad or narrow spectrum of activity.
Many of the current organic biocides have two functional group components, a hydrophilic/polar part and a hydrophobic/oil part. Broad-spectrum biocides may require higher hydrophobic elements in order to penetrate biological membranes and achieve their full potency. Hydrophobicity in biocides can be achieved through incorporation of long chain hydrocarbons or aryl groups into the structure of the molecule. However, the current organic biocides used in the pharmaceutical field are focused on improving biocompatibility to reduce the toxicity against human tissues. Discovery of biocides with a desired balance between hydrophilicity and hydrophobicity for its field of use is important and highly challenging.
Benzalkonium cholide (BAC, BAK) is one of the most common and potent biocide being used in the ophthalmic solution. Although necessary for efficacy, the hydrophobic benzyl and long chain hydrocarbons can also cause damage to ocular tissues. The small molecule of BAC also facilitates penetration and accumulation readily into contact lens and causes irritation when worn in the eye.
For their potential in overcoming some of the disadvantage of the smaller organic monomeric compound described above, polymeric quaternary ammonium compounds has been investigated for a number of years.
For example, British Patent No. 536,017 (Aug. 30, 1941), assigned to E. I. DuPont de Nemours (the “DuPont Patent”), discloses linear polymeric quaternary ammonium compounds and methods for their preparation. The compounds of the DuPont Patent were envisioned to be useful in photographic processing, to treat leather, as mold inhibitors and pesticides, and as modifying agents. There is, however, no mention of use of these compounds as disinfectants or preservatives in pharmaceutical products.
U.S. Pat. No. 3,931,319 (Jan. 6, 1976), U.S. Pat. No. 4,001,432 (Jan. 4, 1977) and U.S. Pat. No. 4,012,446 (Mar. 15, 1977), all issued to Green, et al., disclose a group of high molecular weight “capped” linear polymeric quaternary ammonium compounds found to be effective microbiocides (antimicrobials). In a continuation-in-part application, now U.S. Pat. No. 4,027,020 (May 31, 1977), Green, et al. disclose a process for making randomly capped linear polymeric quaternary ammonium compounds; that is, the polymers produced by the improved process include those with very short chain lengths as well as those having relatively long chain lengths. These compounds were also found to have antimicrobial activity.
U.S. Pat. No. 4,407,791 (Oct. 4, 1983) and U.S. Pat. No. 4,525,346 (Jun. 25, 1985), both issued to Stark, disclose disinfecting solutions for contact lenses, wherein the aqueous solutions contain the Green, et al. polymers, including the compound polyquaternium-1, commercially known as Onamer M® or PolyQuad®.
U.S. Pat. No. 4,110,263 (Lindemann et al.) describes mild cleansing compositions containing alkyleneoxylated bisquaternary ammonium compounds.
U.S. Pat. No. 4,581,058 (Apr. 8, 1986) describes polyalkyleneurea containing quaternary ammonium antimicrobial agents.
U.S. Pat. No. 5,380,303 (Jan. 10, 1995) describes polyoxyalkylene containing quaternary ammonium antimicrobial agents.
U.S. Pat. No. 6,528,048 (Mar. 4, 2003) describes polyhydroxyalkylene containing quaternary ammonium antimicrobial agents.
U.S. Pat. No. 8,093,352 (Jan. 10, 2012) describes polyalkyene oxide containing quaternary ammonium antimicrobial agents.
U.S. Pat. No. 8,309,679 (Nov. 13, 2012), U.S. Pat. No. 8,106,151 (2012), U.S. Pat. No. 7,999,064 (2011), and U.S. Pat. No. 7,705,112 (2010) describe novel methods of making quaternary ammonium antimicrobial agents with improved efficacy and minimum cytotoxicity.
U.S. Pat. No. 8,431,751 (Apr. 30, 2013) describes polymeric quaternary ammonium compounds with vicinal hydroxyl groups as antimicrobial agents.
However, the PolyQuad® has limited antimicrobial efficacy, especially against fungi and mold, while polyhexamethylene biguanide is known to be irritating to ocular tissues. All of the prior art are related to linear polymeric quaternary ammonium compounds and none of branched polymeric quaternary ammonium compounds are disclosed. There still exists a need for biocides with suitable combination of the following: an effective balance of hydrophobic and hydrophilic elements; useful antimicrobial activity; non-irritating; low toxicity; compatibility with the materials and tissue with which they come into contact.